Dual Role of NRF2 in Shaping Pancreatic Premalignant Tumors

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal cancers, with survival rates stubbornly low despite advances in treatment. Intraductal papillary mucinous neoplasm (IPMN) emerges as a distinct premalignant pathway, separate from the more commonly studied pancreatic intraepithelial neoplasia (PanIN). The ability to detect IPMN through imaging before malignant progression offers a transformative opportunity for early intervention in pancreatic cancer. However, the molecular determinants driving the formation of different premalignant lesions remain incompletely understood. Our study uncovers a previously unrecognized role for NRF2, a master regulator of redox homeostasis, in shaping the fate of pancreatic precursors. While NRF2 is known to promote PanIN formation and sustain PDA, we discovered a striking decrease in active NRF2 levels in human IPMN compared to PanIN and PDA. Using a conditional NRF2 knockout mouse model, we further demonstrate that NRF2 loss significantly increases the development of IPMN-like cystic tumors in KRASG12D-mutant pancreatic epithelium, revealing an unexpected role of NRF2 in suppressing IPMN. Intriguingly, while NRF2 promotes PanIN formation through redox-dependent mechanisms, its suppression of IPMN operates via a distinct pathway: the transcriptional repression of SPDEF and MUC6, both key markers of IPMN. These findings illuminate the dual and context-dependent roles of NRF2 in pancreatic tumorigenesis, providing novel insights into the molecular underpinnings of lesion-specific progression in PDA.

ORGANISM(S): Mus musculus

PROVIDER: GSE289513 | GEO | 2025/05/17

REPOSITORIES: GEO